Table 1.
Anti-CSC ADCs.
| Target: ADC name | Linker: Cleavable/uncleavable | Cytotoxin: Antimitotic, DNA binder | Developmental stage Stage, ClinicalTrials.gov identifiers, results if available | References |
|---|---|---|---|---|
| ADCs AGAINST MARKERS EXPRESSED ON CSC | ||||
| DLL3: rovalpituzumab tesirine | Cleavable (dipeptide) | DNA binder (PBD dimer) | Phase III, NCT03061812, vs. topotecan in DLL3+ advanced or metastatic SCLC at first disease progression after platinum chemotherapy Phase III, NCT03334487, evaluating the safety for third-line and later treatment of relapsed or refractory SCLC Phase II, NCT02674568, as third-line and later treatment for subjects with relapsed or refractory DLL3+ SCLC Other phase I/II studies in patients with DLL3+ SCLC (NCT02819999, NCT02874664) or SCLC and other solid tumors (NCT02709889) |
(30, 31) |
| Protein tyrosine kinase 7 (PTK7): PF-06647020 | Cleavable (dipeptide) | Antimitotic (Aur0101) | Safety study, NCT03243331: with gedatolisib in TNBC Phase I, NCT02222922: in adult patients with advanced solid tumors |
(35) |
| Ephrin-A4 (EFNA4): PF-06647263 | Cleavable (hydrazone) | DNA binder (calicheamicin) | Phase I, NCT02078752: in patients with advanced solid tumors | (36) |
| IL-3 receptor α chain (CD123): SGN-123 | Cleavable (dipeptide) | DNA binder (PBD dimer) | Phase I, NCT02848248, in AML patients. Study terminated, presumably no longer in active development. | (37) |
| 5T4: PF-06263507 | Non-cleavable (maleimidocaproyl) | Antimitotic (MMAF) | Phase I, NCT01891669, no objective responses were observed | (38, 39) |
| 5T4: MEDI-0641 | Cleavable (dipeptide) | DNA binder (PBD dimer) Antimitotic (tubulysin) |
Not reported | (40, 41) |
| 5T4: H6-DM4 | Cleavable (SPDB) | Antimitotic (DM4) | Not reported | (42) |
| LGR5 | Cleavable (dipeptide) Non-cleavable (malemidopropionyl) |
Antimitotic (MMAE) Antimitotic (MMAE) |
Not reported Not reported |
(43) |
| LGR5 | Cleavable (dipeptide) Cleavable (acid-sensitive) |
Antimitotic (MMAE) DNA binder (PNU159682) |
Not reported Not reported |
(44) |
| ANTITUMOR ADCs THAT WERE SHOWN TO HAVE ANTI-CSC ACTIVITY AT A LATER STAGE | ||||
| HER2: T-DM1, ado-trastuzumab emtansine | Non-cleavable | Anti-mitotic (DM1) | FDA-approved for the treatment of HER2-positive metastatic breast cancer. | (45) |
| CD33: gemtuzumab ozogamicin | Cleavable (hydrazone) | DNA binder (calicheamicin) | FDA approval in 2000 for the treatment of AML. Voluntarily withdrawn in 2010 due to safety concerns. Recently reapproved. | (46) |
| NCAM (CD56): lovortuzumab mertansine | Cleavable | Anti-mitotic (DM1) | It was in development as antitumor agent, not specifically as anti-CSC agent. Development now halted due to disappointing results in lung cancer patients | (47, 48) |
ADC, antibody-drug conjugate; AML, acute myeloid leukemia; CSC, cancer stem-like cells; DLL3, Delta-like ligand 3; EFNA4, Ephrin-A4; FDA, Food and Drug administration; HER2, human epidermal growth factor receptor 2; LGR5, leucine-rich repeat-containing, G protein-coupled receptor 5; MMAE, monomethyl auristatin E; NCAM, neural cell-adhesion molecule; PBD, pyrrolobenzodiazepine; PTK7, protein tyrosine kinase 7; SCLC, small-cell lung cancer.